1. Field of the Invention
The present invention relates to compounds with antibiotic activity, which are useful for treating infectious diseases, and relates more particularly to compounds of formula 
in which Het is a biheterocyclic system; to pharmaceutically acceptable salts thereof and to pharmaceutical compositions containing them as active principle.
2. Description of Related Art
International patent application WO96/18633 in the name of the Applicant discloses compounds with antibiotic activity, which have the following general formula: 
in which
A is a phenyl or a 5- or 6-membered heterocycle containing one or more hetero atoms chosen from nitrogen, oxygen and sulphur, optionally substituted with 1 to 3 groups, which are the same or different and are chosen from linear or branched C1-C4 alkyl or alkoxy groups, C1-C2 cycloalkenedioxy groups, C1-C4 alkylsulphonyl groups, phenyl, phenoxy, hydroxyl, carboxyl, nitro, halo and trifluoromethyl groups; R1 and R2 are the same or different hydrogen atom or linear or branched C1-C4alkyl group; n is 1 or 2; m is an integer from 1 to 8; r is an integer from 2 to 6; R3 is hydrogen or methyl.
We have now found that, by introducing a biheterocyclic group as a substituent (xe2x88x92A) at the end of the chain in the compounds of formula (II) of the above-mentioned international patent application, it is possible to obtain a class of erythromycin derivatives which have a particularly broad spectrum of activity and a long duration of action, thereby making them extremely useful in antibiotic therapy.
It is an object of the present invention to provide a compound of formula 
in which
R and R1 are the same or different hydrogen atom or linear or branched C1-C4 alkyl group; Het is a biheterocyclic group of formula 
in which
R2 is a saturated or unsaturated 5- or 6-membered heterocycle containing from 1 to 3 hetero atoms chosen from nitrogen, oxygen and sulphur, optionally substituted with 1 or 2 substituents chosen from C1-C3 alkyl groups, hydroxyl groups, oxo (xe2x95x90O) groups, nitro groups, C1-C3 alkoxycarbonyl groups, aminocarbonyl groups, mono- or di- C1-C3 alkylaminocarbonyl groups and C1-C3 alkylcarbonyl groups; and pharmaceutically acceptable salts thereof.
The term xe2x80x9clinear or branched C1-C4 alkyl groupsxe2x80x9d means a group chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl and sec-butyl.
The term xe2x80x9csaturated or unsaturated 5- or 6-membered heterocycle containing from 1 to 3 hetero atoms chosen from nitrogen, oxygen and sulphurxe2x80x9d means heterocycles such as pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, isothiazole, isoxazole, oxazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole and thiadiazole, and partially or totally saturated forms thereof.
Preferred compounds of formula (I) are compounds in which R and R1 are the same or different hydrogen atom or methyl group.
Among this class, those compounds which are particularly preferred are compounds in which R2 is a saturated or unsaturated 5- or 6-membered heterocycle containing from 1 to 3 hetero atoms chosen from nitrogen, oxygen and sulphur, optionally substituted with 1 or 2 substituents chosen from C1-C3 alkyl groups, hydroxyl groups, oxo (xe2x95x90O) groups, nitro groups and C1-C3 alkylcarbonyl groups.
Even more preferred compounds are those of formula (I) in which R and R1 are the same or different hydrogen atom or methyl group and R2 is a heterocycle chosen from thiazole, thiadiazole, thiophene, imidazole, isoxazole, triazole, pyrazole and oxazolidine, optionally substituted with a methyl group or with an xe2x95x90O group.
Among this class, those compounds which are particularly preferred are the compounds in which R and R1 are hydrogen and the compounds in which R is methyl and R1 is hydrogen.
Examples of pharmaceutically acceptable salts of the compounds (I) are salts with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulphuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, benzoic acid, succinic acid and glutaric acid.
The preferred salt is the hydrochloride.
The compounds of formula (I) of the present invention can be prepared by various alternative synthetic methods similar to the method already described in patent application WO96/18633.
In particular, the compounds of formula (I) are synthesized by reacting an intermediate of formula 
in which R and R1 have the meanings given above;
with an aldehyde of formula 
in which R2 has the meanings given above.
The intermediate of formula (III) can be prepared by alternative synthesis processes.
For example, a preferred process for preparing the intermediates of formula (III) in which R and R1 are hydrogen atoms is given in the scheme below: 
in which
Z and Z1, the same or different, represent a protecting group;
R3 represents a methyl or p-tolyl group.
The synthesis involves oxidation of the appropriately protected aminohexanol (V) into the corresponding aldehyde by treatment with an oxidizing agent, preferably sodium hypochlorite.
Condensation of the aldehyde (VI) with 2-aminoethanol followed by reduction of the intermediate imine, preferably with NaBH4, gives compound (VII).
After also protecting the second amino group, compound (VIII) is treated with mesyl or tolyl chloride to activate the OH group and allow subsequent condensation of the activated compound (IX) with erythromycin A oxime. Removal of the protecting groups from compound (X) gives the intermediate (III-A).
Another preferred synthetic process for preparing the intermediates of formula (III) in which R is alkyl and R1 is hydrogen is given in the scheme below: 
in which Z and Z1 have the meanings given above and R is an alkyl group.
The synthesis involves firstly protecting the 2-amino ethanol (XI), and treatment of compound (XIII) with mesyl or tolyl chloride to activate the OH group and allow subsequent condensation of the activated compound (XIII) with erythromycin A oxime to give compound (XIV).
After deprotecting the amino group, compound (XV) is treated with compound (VI) and the intermediate (XVI) thus obtained is deprotected to give compound (III-B).
The compounds of formula (I) of the present invention have a broad spectrum of activity in vitro against Gram-positive and Gram-negative microorganisms.
This activity is greater than that of azithromycin on strains of Staphylococcus spp. and Streptococcus pneumoniae with inducible resistance to erythromycin (Example 21).
However, the aspect which mainly characterizes the compounds of the present invention is their appreciable duration of action in vivo. Specifically, as reported in Example 22, the therapeutic efficacy of the compounds of formula (I) was compared with that of clarithromycin.
It is clear from the comparison that the compounds of formula (I) have prolonged activity on the lungs, unlike clarithromycin.
The advantage of prolonged therapeutic efficacy is clear to those skilled in the art, since, from a practical viewpoint, it allows the dose of antibiotic to be reduced significantly and/or allows the interval between consecutive administrations to be increased, for example going from a prescription plan which involves two dosage intakes per day to a plan which involves only one dosage intake per day.
The compounds of formula (I) can be used in human and veterinary therapy.
For use in therapy, the compounds of formula (I) can be used in a pharmaceutical form which is suitable for oral or parenteral administration.
It is therefore a further object of the present invention to provide a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I) or of a salt thereof mixed with a pharmaceutically acceptable vehicle.
For the treatment of specific infections, the compounds of formula (I) may also be combined with a therapeutically effective amount of another active principle.
The following examples are now given for the purpose of illustrating the present invention more clearly.